title: JAK2V617F leads to intrinsic changes in platelet formation and reactivity in a knock-in mouse model of essential thrombocythemia.
abstract: The principal morbidity and mortality in patients with essential thrombocythemia (ET) and polycythemia rubra vera (PV) stems from thrombotic events. Most patients with ET/PV harbor a JAK2V617F mutation, but its role in the thrombotic diathesis remains obscure. Platelet function studies in patients are difficult to interpret because of interindividual heterogeneity, reflecting variations in the proportion of platelets derived from the malignant clone, differences in the presence of additional mutations, and the effects of medical treatments. To circumvent these issues, we have studied a JAK2V617F knock-in mouse model of ET in which all megakaryocytes and platelets express JAK2V617F at a physiological level, equivalent to that present in human ET patients. We show that, in addition to increased differentiation, JAK2V617F-positive megakaryocytes display greater migratory ability and proplatelet formation. We demonstrate in a range of assays that platelet reactivity to agonists is enhanced, with a concomitant increase in platelet aggregation in vitro and a reduced duration of bleeding in vivo. These data suggest that JAK2V617F leads to intrinsic changes in both megakaryocyte and platelet biology beyond an increase in cell number. In support of this hypothesis, we identify multiple differentially expressed genes in JAK2V617F megakaryocytes that may underlie the observed biological differences.
authors.affiliation: National Health System Blood and Transplant, Cambridge, United Kingdom;
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Hobbs
authors.forename: Harriet
authors.initials: H
authors.lastname: Manning
authors.forename: Cavan
authors.initials: C
authors.lastname: Bennett
authors.forename: Louella
authors.initials: L
authors.lastname: Vasquez
authors.forename: Sonia
authors.initials: S
authors.lastname: Severin
authors.forename: Lauren
authors.initials: L
authors.lastname: Brain
authors.forename: Alexandra
authors.initials: A
authors.lastname: Mazharian
authors.forename: Jose A
authors.initials: JA
authors.lastname: Guerrero
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Green
authors.forename: Steve P
authors.initials: SP
authors.lastname: Watson
authors.forename: Cedric
authors.initials: C
authors.lastname: Ghevaert
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000201:enzymology* / Q000473:pathology; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D053614:Janus Kinase 2 / Q000097:blood* / Q000235:genetics*; D008533:Megakaryocytes / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000097:blood* / Q000235:genetics*; D009154:Mutation; D010974:Platelet Aggregation / Q000235:genetics; D011994:Recombinant Proteins / Q000097:blood / Q000235:genetics; D013920:Thrombocythemia, Essential / Q000097:blood* / Q000201:enzymology / Q000235:genetics*; D034061:Thrombopoiesis / Q000235:genetics
chemical_list: D050505:Mutant Proteins; D011994:Recombinant Proteins; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2